Legius

Legius syndrome, also known as a neurofibromatosis type 1–like syndrome, is a rare autosomal dominant genetic disorder characterized by pigmentary features that resemble NF1. It is caused by loss-of-function variants in SPRED1, a gene located on chromosome 15q13.3. SPRED1 encodes a protein that normally inhibits the Ras-MAPK signaling pathway; when haploinsufficient, this regulation is reduced, leading to the observed clinical features.

The most common signs are café-au-lait macules and axillary or inguinal freckling, often present from birth or early childhood. Many individuals have normal growth and development, but some may experience mild learning difficulties or speech delay. Additional features can include macrocephaly and occasional mild skeletal or dental anomalies. Unlike NF1, Legius syndrome typically lacks neurofibromas and Lisch nodules, and there is usually no increased risk of tumors associated with NF1.

Diagnosis is based on clinical features and genetic testing. A pathogenic SPRED1 variant confirms the diagnosis. If NF1 testing is performed and negative, but café-au-lait spots persist with freckling, SPRED1 testing may be indicated to distinguish Legius syndrome from NF1. Differential diagnosis includes neurofibromatosis type 1 and related Ras-MAPK pathway disorders.

Management focuses on supportive care and surveillance for developmental or learning issues, with appropriate educational support as needed. Cancer surveillance typical for NF1 is not routinely required in Legius syndrome, given the lower risk of neurofibromas and related tumors. Genetic counseling is advised, given the autosomal dominant inheritance and the possibility of de novo variants.

Prognosis is generally favorable, with most individuals leading normal or near-normal lives, though variability in cognitive and physical features can occur.